SUMMARY Dental caries is the most prevalent chronic disease worldwide, leading to partial loss of dental tissue and teeth. The most conservative treatment of missing dental tissue is direct resin composite restoration. The annual failure of resin composite restorations is high, lasting an average of 6 years. The primary reason for failure is the development of secondary caries, followed by defective margins and fracture. An estimated 50% of resin composite restorations done by practitioners replace failed restorations, leading to a vicious restorative cycle with increasing complexity, poor prognosis for the tooth, and high treatment costs. Resin-based restorations rely on micro-mechanical adhesion to enamel and dentin structures. Dentin is of great importance as it is the bulk of the tooth and is tightly connected with the pulp tissue. It is well known that components of the dentin organic matrix play major roles in the formation and sustainability of the dentin-resin bonds. With a primary focus on dentin preservation and reinforcement, the ultimate goal of this research proposal is to develop biologically inspired and biocompatible approaches to create effective and stable dentin-dentin interfaces to increase the longevity of resin composite restorations reducing the need for replacement. Our interdisciplinary research group has established a strong foundation knowledge in the biomimetic use of plant polyphenols to enhance the mechanical properties and reduce the susceptibility to enzymatic biodegradation of type I collagen; an integral component of the dentin-resin composite interface. Specifically, we observed that structurally unique chemical entities of oligomeric proanthocyanidin (OPAC) can elicit desirable dentin matrix modifications of significant impact in the broad reparative/regenerative dentistry field; and of promising application for other collagen based tissues. The sources of OPACs are industrial waste and/or by-products, making them highly sustainable from both economic and environmental perspectives. In this proposal renewal, we will extend beyond the initial outcomes (Y1-5) to achieve a tailored biological response of high translational impact by the development of innovative phytoanalytical methods to produce and standardize high potency mid-size OPACs; reveal a novel wet bioadhesion mechanism of dentin-OPACs-resins; bio-integrate resin- dentin components with built-in on demand capability; and control key localized biological tissue responses for their pre-clinical usage. Three thematic aims are proposed to achieve the ultimate goal of this proposal include: Phytochemistry of Highly Defined Mid-Size OPAC Mixtures for Two Priority Plants (Aim 1); Physicochemistry: Unraveling the Complexity of Dentin-OPACs-Resin Biointerface (Aim 2); Local Biological Tissue Response to OPAC Mixtures Under Simulated Clinical Conditions (Aim 3). The aims will be carried out by an established interdisciplinary and collaborative research team.